Process for the preparation of lacosamide

Abstract

Present invention relates to an improved and commercial process for the preparation of lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropanamide) of formula (I). Present process utilizes high purity crystalline solids of formulae (XXXII) and (XIII) as key intermediates. Lacosamide is indicated for the adjunctive treatment of partial onset seizures in patients aged at least 17 years.

We claim: 
     
       1. Improved process for the preparation of lacosamide of formula-I, 
       
         
           
           
               
               
           
         
         which comprises: 
       
       (i) reaction of D-serine with Boc anhydride in the presence of a base in aqueous medium at −10 to 30° C. to get N-Boc derivative of formula-XVI, 
       
         
           
           
               
               
           
         
       
       (ii) reaction of N-Boc derivative of formula-XVI with dimethyl sulphate in the presence of a base in aqueous medium at 0-30° C. to get the compound of formula-XVII, 
       
         
           
           
               
               
           
         
       
       (iii) reaction of compound of formula-XVII with trifluoroacetic acid at 0-60° C. to get the novel trifluoroacetate salt of O-methyl-D-serine of formula-XXXII, 
       
         
           
           
               
               
           
         
       
       (iv) acetylation of compound of formula-XXXII with acetic anhydride or acetyl chloride to get the compound of formula-XIII, 
       
         
           
           
               
               
           
         
       
       (v) amidation of compound of formula-XIII with benzylamine via a carbamate intermediate at −100 to 35° C. to get crude lacosamide of formula-I, 
       
         
           
           
               
               
           
         
       
       (vi) recrystallization of crude lacosamide from a solvent to get pharmaceutically acceptable grade lacosamide. 
     
     
       2. The process according to  claim 1  wherein the base used in step (i) is selected from sodium or potassium hydroxide, carbonate, bicarbonate, etc., preferably sodium or potassium hydroxide, more preferably sodium hydroxide. 
     
     
       3. The process according to  claim 1  wherein the amount of base used in step (i) is selected from 2-3 equivalents to the amount of D-serine. 
     
     
       4. The process according to  claim 1  wherein the base used in step (ii) is selected from sodium or potassium hydroxide, carbonate, bicarbonate, etc., preferably sodium or potassium hydroxide, more preferably sodium hydroxide. 
     
     
       5. The process according to  claim 1  wherein the acid used for neutralization of base in step (ii) is selected form organic acid such as acetic, propionic, oxalic, citric acid or a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, preferably citric acid or sulfuric acid. 
     
     
       6. The process according to  claim 1  wherein the solvent used for extraction of compound of formula-XVII in step (ii) is selected from ethers such as diethyl ether, diisopropyl ether, methyl isobutyl ether, methyl tert-butyl ether, esters such as ethyl acetate, isopropyl acetate, halogenated solvents such as methylene chloride, chloroform, hydrocarbon solvents such as cyclohexane, toluene, preferably ethyl acetate or diisopropyl ether. 
     
     
       7. The process according to  claim 1  wherein the mole equivalents of trifluoroacetic acid used in step (iii) is 5 to 20 moles equivalents, preferably 10 mole equivalents. 
     
     
       8. The process according to  claim 1  wherein the mole equivalents of acylating agent used in step (iv) is 1 to 5 mole equivalents, preferably 2 mole equivalents. 
     
     
       9. The process according to  claim 1  wherein the acylating agent used in step (iv) is acetic anhydride. 
     
     
       10. The process according to  claim 1  wherein the preferred temperature of reaction in step (v) is −40 to 30° C., more preferably −20 to 30° C. 
     
     
       11. The process according to  claim 1  wherein the solvent used in crystallization of lacosamide is selected from ethers such as diethyl ether, diisopropyl ether, methyl isobutyl ether, methyl tert-butyl ether, esters such as ethyl acetate, isopropyl acetate, halogenated solvents such as methylene chloride, chloroform, hydrocarbon solvents such as cyclohexane, toluene, preferably ethyl acetate or diisopropyl ether.